Molecular therapy for multiple myeloma

Background and Objectives. Several molecular and cytogenetic advances have suggested novel therapeutic strategies that could help roach an eventual cure for multiple myeloma (MM). Evidence and Information Sources. Identification of novel, MM-specific molecular targets should pave the way for drugs that can specifically attack the neoplastic cells while sparing the normal ones. Drugs that alter the marrow microenvironment - such as bisphosphonates, proteasome inhibitors (e.g. PS-341/LDP341), lactacystin or LLNV compounds - induce apoptosis or G1 growth arrest and alter the adhesion of MM cells to marrow stroma. These drugs that modify the microenvironment have a more solid scientific basis and may, therefore, have more realistic implications in MM treatment. Of these, novel vascular endothelial growth factor (VEGF) inhibitors, such as SU5416 and SU6668, block tumor-cell adhesion and could disrupt MM cell proliferation. Similarly, tyrosine kinase inhibitors (TKI) such as fibroblast growth factor receptor (FGFR) inhibitors, may serve when the FGFR3 gene is overexpressed due to the t(4;14)(p16.3;q32) and/or is activated by point mutations. In cases carrying the translocation and expressing the IgH/WHSC1-MMSET hybrid transcripts, histone deacetylase (HDAC) inhibitors could be useful, but their possible clinical use needs to be supported by more biological studies. Tumor necrosis factor α-related apoptosis-inducing ligand (TRAIL) induces apoptosis in MM cell lines and primary cells. The proliferative signaling pathway of FGFR3 is mediated by Ras (Ras-activating mutations are frequently found in MM), which presents a possible target for farnesyltransferase inhibitors (used alone or in association with IFN-α). Perspectives. In several of these options, proclinical studies have proved encouraging, and clinical trials are now getting underway. ©2001, Ferrata Storti Foundation.